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of
Cryopreserved
DOI:
http://dx.doi.org/10.5772/104451
Skin
from
Live
Donors
and
Total
Skin
Allografts
in
the
Surgery
of…

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Integrated Optical Coherence
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Chapter 12
Tomograph
y and Deep Learning
for Evaluating of the Injectable
Hydrogel on Skin Wound Healing
QingliangZhao and LinChen
Abstract
Recently hydrogels and the treatment of skin wounds based on hydrogel dressings
have become one of the research hotspots in the field of skin trauma. In this chapter,
we focus on the materials and methods of hydrogel preparation, and discuss the
properties that hydrogels should possess for the treatment of wounds. Moreover, we
discuss the potential of non-invasive optical imaging techniques in the assessment
of cutaneous wound healing. The research results of the application of non-invasive
optical techniques such as diffuse reflectance spectroscopy (DRS) and optical coherence tomography (OCT) in scar identification, skin bruising, and skin and vascular
structure identification are reviewed. Furthermore, we further discuss the superiority and potential of current artificial intelligence (AI) technology in dermatological
diagnosis, and analyze the application status of hydrogel in skin wound treatment.
Finally, we believe that the combination of AI and optical imaging technology in the
development and efficacy monitoring of hydrogels will be a promising research direction in the future.
Keywords: hydrogel, OCT, in vivo imaging, artificial intelligence, wound healing
. Introduction
As the largest organ system in the human body, the skin plays a vital role in
maintaining the body’s physiological stability, protecting the skin from external
stimuli, preventing infection, and maintaining fluid balance. Therefore, skin wound
healing is an important step in the survival to complete wound closure [1]. Although
human skin can heal itself after injury, this is limited to superficial wounds. In cases
such as deep burns or diabetes, the wound’s self-healing ability is limited, and supportive methods are needed to accelerate and protect the wound healing process.
Current conventional approaches to wound treatment including the application of
different types of dressings, electrical stimulation therapy, skin grafting, and negative
pressure wound therapy (NPWT) have proven beneficial, but they also have certain
limitations [2].

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Since O. Wichterle et al., reported the first case of hydrophilic gel in 1960, the
results of the application of hydrogel in wound healing have become increasingly
abundant [3–9]. More and more research results show that hydrogels have the ability to deliver drugs, cytokines, and growth factors as carriers, which will greatly
accelerate wound healing. In addition, compared with traditional dressings, the
non-adhesive nature of the hydrogel avoids secondary damage, and its 3D network
structure is conducive to absorbing wound exudate while maintaining an ideal moist
environment [10–13]. In view of this, hydrogels have gradually become ideal wound
dressings in recent years and show good prospects in the treatment of burns and other
skin injuries [14, 15]. In this chapter, we describe advanced hydrogels for wound healing and enhanced skin repair.
. Development of injectable hydrogel
To date, a plethora of biomaterials as wound dressings for different clinical
treatment protocols have been developed, which may be composed of synthetic
or natural materials, or may be a hybrid of the two. Naturally occurring polymers,
such as sodium alginate (SA), chitosan (CS), gelatin, and hyaluronic acid (HA), are
biocompatible and biodegradable, which allow adhesion and coordination of cellular
responses [16]. Unfortunately, natural hydrogels suffer from some limitations, such
as not having strong mechanical properties and significant batch-to-batch variability
[17]. In contrast, synthetic polymers such as polyvinyl alcohol (PVA), polyacrylamide
(PAM), and polyethylene glycol (PEG) have become increasingly popular due to their
strong mechanical properties, customizable structures and low immunogenicity [18].
However, the application of synthetic polymers in the field of biomedicine should
pay attention to the rejection of the body. Therefore, more complex hydrogels were
synthesized. Currently, the material design of hydrogels usually combines natural
biopolymers and synthetic polymers to overcome the limitations brought by a single
polymer [18]. Hydrogels are formed by cross-linking polymer chains dispersed in an
aqueous medium, and the cross-linking methods mainly include physical entanglement, ionic interactions, and chemical cross-linking (Figure ) [19]. Physical cross-
linking is usually non-permanent, not as stable as chemical cross-linking, and has
cross-linking reversibility, but it is sufficient for polymer chains to aggregate to form
gel substances that are insoluble in aqueous media. Due to the covalent bonds between
different polymer chains, chemically cross-linked gels have excellent mechanical
strength because they are mainly connected by covalent bonds, but their preparation requires the addition of chemical initiators or cross-linking agents. It has been
reported that the cross-linking agent has certain toxicity, so the cross-linking agent
used to prepare the hydrogel should be extracted from the hydrogel before use, which
increases the complexity of the use of chemically cross-linked gel [20]. Electron
beam (EB) radiation cross-linking technology can overcome the above defects, which
belongs to the grafting in chemical cross-linking and is more stable than the physical
cross-linking network structure. Furthermore, when using radiation crosslinking,
neither initiators nor crosslinking agents are required, making it safer, softer, and
more stretchable than traditional chemical crosslinking [21]. Work in the late 1990s
showed that hydrogel precursors can be injected via standard syringes without the
need for pre-molding and the use of highly invasive surgical procedures to deliver
the material to the target site. Injectable hydrogels have received increasing attention
in recent years due to their excellent self-healing ability and minimal invasiveness
[22]. Injectable hydrogel technology can better reproduce the complex extracellular

Integrated Optical Coherence Tomography and Deep Learning for Evaluating of the Injectable…
DOI: http://dx.doi.org/10.5772/106006
Figure 1.
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Cross-linking of hydrogels. (a to d) physical cross-linking. (a) Thermally induced entanglement of polymer
chains. (b) Molecular self-assembly. (c) Ionic gelation. (d) Electrostatic interaction. (e) Chemical cross-linking.
Reprinted with permission from reference [19].
environment and maintain cell viability, thereby enabling adequate delivery of cells
and therapeutic small molecules, which enables the development and optimization of
novel therapeutic injectable Hydrogels [23, 24].
Gelatin is inexpensive and readily available and has good cell adhesion [25].
Alginates are commonly used in the treatment of deep second-degree burns due to
their excellent biological properties, exudate absorption potential, and ability to
maintain a moist wound environment [26–28]. In addition, carboxymethyl cellulose
(CMC) contains a large number of carboxymethyl groups, which facilitates polymerization with other material [29, 30]. Their combined strengths make up for the
deficiencies of one or both of these natural polymers for applications.
The EB radiation cross-linking mechanism in Figure is proposed for cross-
linking of injectable 3D-PH. The radiation energy of EB is mainly absorbed by
water in aqueous solution, and the radiation decomposition of water mainly
produces reactive species such as hydroxyl radicals (OH) (Figure a) [32]. Amino
acid residues in gelatin molecules are easily self-oxidized to form aldehyde groups,
and aldehyde groups can cross-link with amino acids on gelatin molecules to form
Schiff bases (Figure b), which is the first cross-linked network. Injectable 3D-PH

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Figure 2.
Mechanism of EB radiation crosslinking of injectable 3D-PH. (a) Ionizing radiation reaction equation of
waterin polymer aqueous solution. (b) Gelatin self-crosslinking to form the fifirst network of injectable 3D-PH.
(c) the crosslinking mechanism of alginate and CMC under EB irradiation. Reprinted with permission from
reference [31].
Furthermore, OH- is considered to be a very reactive species, which can remove H
from alginate and CMC carbon chains, inducing the formation of alginate-derived
radicals, CMC-derived radicals, and HO. Subsequently, the radicals recombine to
form new covalent bonds between the carbon chains (Figure c), which is a second
cross-linked network. Hydrogen bonds formed between the injectable 3D-PH stabilize the chemical structure of the hydrogel. The new bonds formed during electron
beam irradiation made the molecular chains of the hydrogel connect more tightly.
The double-crosslinked network structure triggered by EB and Schiff base can
significantly strengthen the hydrogel. These results demonstrate that EB irradiation cross-linking injectable 3D-PH can form a stable double-cross-linked network
structure [31].
In view of this, our team designed an injectable 3D-PH via EB radiation crosslinking gelatin-alginate-carboxymethyl cellulose solution, which developed by green
materials and facile applicable method (Figure a). In another study, Zhang et al.
synthesized dopamine-modified gelatin@Ag nanoparticles (Gel-DA@Ag NPs)
by chemical grafting for wound healing as shown in Figure b [33]. For the first
time, they found that the biomineralization ability of gelatin can be enhanced with
dopamine-modified gelatin (Gel-DA). This biomineralization-enhancing strategy
provides a new strategy for developing organic and inorganic hybrid multifunctional

Integrated Optical Coherence Tomography and Deep Learning for Evaluating of the Injectable…
DOI: http://dx.doi.org/10.5772/106006
Figure 3.
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Schematic diagram of the preparation of hydrogels. (a) 3D-PH. (b) Gel-DA /GG@Ag hydrogels. Reprinted with
permission from reference [31, 33].
hydrogels. Among the two different materials, gelatin plays different roles, the
former mainly induces platelet activation for wound hemostasis and the latter mainly
acts as a biomineralizer combined with metal nanoparticles, resulting in different
functional localization.
. Design points of hydrogels for wound treatment
Given the characteristics of the wound surface, the goals of wound management
seem obvious, including providing temporary wound coverage, preventing infection,
and relieving scarring [34]. Because bacterial infection can hinder the regeneration
of epithelial cells and the synthesis of collagen, the prevention of wound infection
is an important function of wound dressings [35]. To achieve this function, some
broad-spectrum antimicrobial agents are often added to hydrogels, such as silver ions/
nanoparticles (AgNPs) [36]. Zhang et al. compared the antibacterial properties of
Gel-DA/GG@Ag hydrogels by spread plate method using two hydrogels with only
guar gum (GG) and without silver ions (Gel-DA hydrogel) as the control group. As
shown in Figure b, in the three treatments, the number of bacterial colonies in the
GG and Gel-DA hydrogel did not change significantly, but in the GG@Ag hydrogel
treatment group, the number of colonies of Escherichia coli and Staphylococcus aureus
was significantly reduced, reflecting the antibacterial effect of AgNPs.” Guo et al.
synthesized a hydrogel TS-Gel-Ag-col with antibacterial and anti-inflammatory functions for wound treatment, which was prepared by muco-mimetic poloxamer 407
(F-107), polyvinylpyrrolidone, and dencichine/chitosan dialdehyde synergistic crosslinked aggregated collagen nanofibers decorated with silver nanoparticles [37]. The
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